Manufacture of esters of the hydrocinchona alkaloids.



UNITED STATES PATENT- OFFICE.

I HEINRICH THRON, 0F FRANKFORT-ON-THE-MAIN, GERMANY, ASSIGNOR TO,VERE- INIGTE CHININFABRIKEN ZIMMER & 00., Gr. M. B. 1 1., OF FRANKFURT-OIl-THE- MAIN, GERMANY.

MANUFACTURE OF ESTERS OF THE HYDROCINCHONA ALKALOIDS.

Specification of Letters Patent.

Patented Dec. 31, 1912.

. Hailrawing. Original application filed December 23, 1911, Serial No. 667,447. Divided and this application filed June 18, 1912.

To all whom it may concern:

Be it known that I, HEINRICH THRON, a subject of the Emperor of Germany, and resident of Frankfort on the Main, Germany, have invented certain. new and useful Improvements in the Manufacture of Esters of the Hydrocinchona Alkaloids, of which the following is a specification.

I have succeeded in producing esters of hydro cinchona alkaloids such as hydroquinin, hydrocinchonin, hydrocinchonidin, hydrocuprein or hydroapoquinin, and the like, by means of organic acids, which esters are easily crystallizing and constitute tasteless bodies which are valuable medicaments.

According to this invention I cause, for

instance, the chloride, or the anhydrids, or the phenol esters, of the organic acids, of which it is desired to obtain the correspond ing hydrocinchona-alkaloid esters, to reacton the corresponding hydrocinchona-alkaloids; their salts, or their, oxymagnesium haloid compounds, or I may start from the cinchona alkaloid esters and treat these with hydrogen in the presence of metals of the platinum group, or of colloidal solutions of these metals. The hydrocinchona-alkaloid esters prepared according to this invention differ chemically from the known cinchona alkaloid esters in being much more stable toward potassium permanganate. In therapeutics they have, over the last named esters, the advantage that they contain, as active compounds, hydrocinchona-alkaloids which have specific medical actions. Compared with the free hydro-cinchona-alkaloids and salts thereof they have the advantage that they have no bitter taste.

The following examples illustrate the invention, but it is not limited to these examples. The parts ai'eby weight.

E wample 1-Hydr0gminin ethyl carbonate.l0 parts of quinm-ethyl-carbonate are dissolved in 14 parts of twenty per cent.

' sulfuric acid and eighty parts of water and troleum-benzin and water.

maining on distilling off the other is dissolved in one hundred parts of hotpetroleum-benzin. On cooling the solution the hydroquinin-et-hyl-carbonate crystallizes in cording to the process more fully described in the parent application, of which the present application is a division.' I

Emample 2Pa.ra amino beneoyl hydroguinin.-100 parts of para-amino-benzoylquinin are dissolved in 400 parts of water and 30 parts of sulfuric acid, 1 part of palladium black is added and the mixture is shaken with hydrogen until the gas ceases to be absorbed. Then the palladiumis separated by filtration, the base precipitated with ammonia and recrystallization effected in a mixture of equal parts of benzene and etroleum benzin. The body thus obtained has the form of colorless and tasteless needles which melt at from 155, to 157.5 centigrade and-are readily soluble in-alcohol or chloroform but. difficult-ly soluble in petroleum-benzin and water.

Emample 3-Hydr0 cz'nchom'n ethyl carb0nate.30 parts of cinchonin-ethyl-carbonate are dissolved in 160 parts of alcohol; the mixture is mixed with a solution of 0.1 part of colloidal palladium in 60 parts of water and shaken with hydrogen at a pressure of a few meters of water until the volume of the hydrogen no longer decreases.- The greater part of the alcohol is then distilled off, and the residue is dissolved in. dilute sulfuric acid so that the palladium is precipitated.- The mass is filtered. and the filtrate mixed with ammonia in excess and the base is absorbed in ether. After distilling off the ether the mass is dissolved in dilute alcohol out of which the hydrocinchoninethyl-carbonate crystallizes in fine, colorless and tasteless needles which melt at 134 centigrade.-. It is readily soluble in alcohol,

or chloroform, but is difiicultly soluble in pe- In sulfuric acid solution it is, in contradistinction to cinchonin-ethyl-carbona'te, stable toward potasice Uilier products than those above 1 'lionocl can 13.

9.150 be producoC-l either by i the COI'EFGSfifilflhi drocincliona, Gil lmloio ,or by hyfll on1 ilie corresponding cinchona alkaloid dSlGin. Thus the hyclroquinin caii'bonato an'rl tho ethyl-hydro (.fliiprlllfiijl'l 'l CEil'lJOIllllii can be grofluceol, example according "to the 172F005. more fully described and illustrated. by specific examples in the parent application Serial N o fifil'gll'i of which the present application is a division.

The liyflroquinin cor'lionnl'o is ancl almost tasteless pow? in alcohol and chlorofo P soluble in polroloizm-lvow lov ng a yellow liempatlilio :1 Ellis pomianganoto in acid solution. its acid sulfate salt ci'fig'stalliziei; in neerllo slmpecl crystals which i'eilalily soluble Wot-e13 but clii'licultly soliililo in alcohol ill-1o ethyl liyclroouproin ethyl forms colorless pow soluble in alcohol zmo v. 11 (limcultly soluble in PBil'OlG'Ll Jmlzlll and. Wator. Its solioylate is readily crystalliza clo in fiche form of colorless m' ysii-als WlllQll melt 51!; from 138 i0 C9 and. are ma i soluble in alcohol and benzene but are more cliilioultly soluble in other and very cliffoultly soluble in PEllOlBlUIHbGBZlH.

Hz'z'vingf llldi described my invention, W113i. claim is:

1. The process of produ-rzing aciclyl esters of iiydrocincliona alkaloids which 'con'iprises reducing the corresponoing aoiilyl esters of he cinchona. alkaloids Willi hydrogen in the pieslonce a catalylio metal of the platinum orless m of the platinum group.

ll ho process of producing; carbonates; 01'? l alkaloids Wnml'i compi ses carbonates of .filffl h f. x; w, 4 i. Elmo process; oi. pi o ciuoingoaioomles oi.

ll rooinohonfl allmioils which comprises; (EMILE the 6 none 21g oaroona'tes of oii'ichoim alkaloids li rclrogen in prosenoe oft oollolclm. ooluliion 01 a. metal.

he platinum group 7 Tllfi PK'Gi-QSS 01 pr-coming carlmim lei, readily soluble which comprises reducing the icing carbonates of quiniii. with on in the pyesenco of a colloidal solution metal oi. the platinum group.

'2'. The proceqs of producing allryl carbon-- ates: of h yclrocinchoiia, alkaloids which oompiises; rodooii'ig the corresponding alliyl carbonzziaes of the cinooonrif alkaloids with by the presence of a catalytic metal o. group,

s of produoiiig allay oai'lioo mess oi hyalrooiiinin which. comprises rocluoonrresponfling zillr' l mrlaooatos of qumm "with caml 'tio metal of the p 9., As now procluoltg' L :rworog carbonate-s of hyiili'ooiiionono colorless :incl lasloi'ms booties yearlily iulolo in alcohol. and chloroform bu; rliiib solublo in petroleum bonzin and walzer. product; who heroin ClE-Sulll'JEd hy l1oquini, l v ng colorless bodies Tea-5 so lo Z'iCl chloroform bill; fliiiicul fily soluble in petroleum benzin anal. Water.

11. As new products the heroin desoi'iberl alkyl carbonates of the hyoliocinclzom; alligloiclg being colorless and tasieless boclios, readilysoluble in alcohol am? but clillicultly soluble in pet? and Watei.

new products the liiemi'ii ii -ascribed alk il oar bonates of liyoiroquiniii, being colorless and tasteless boios, be? y soluble in L lililculily soln alo 1o. new

alcohol chloroform law in petroleum bemrin and As new products the ethyl 'sarltwoiiates of the li lrocincliona. allmloiols, ls-eow oolorless anal tasteless bodies, roaclily soluble in alcohol and chloroform but ""fiioultly solulile in petroleum benzin will.

14C a new f lzydroquin? st iastPle-ss oz" hing-2 m 

